Essential role for autophagy protein VMP1 in maintaining neuronal homeostasis and preventing axonal degeneration

Panpan Wang,Weidong Le,Ying Wang,Han-Ming Shen,Congcong Jia,Huaibin Cai,Xinyao Liu,Haifeng Wu,Xi Chen,Yuanyuan Wang

doi:10.1038/s41419-021-03412-5

Abstract

Vacuole membrane protein 1 (VMP1), the endoplasmic reticulum (ER)-localized autophagy protein, plays a key role during the autophagy process in mammalian cells. To study the impact of VMP1-deficiency on midbrain dopaminergic (mDAergic) neurons, we selectively deleted VMP1 in the mDAergic neurons of VMP1fl/fl/DATCreERT2 bigenic mice using a tamoxifen-inducible CreERT2/loxp gene targeting system. The VMP1fl/fl/DATCreERT2 mice developed progressive motor deficits, concomitant with a profound loss of mDAergic neurons in the substantia nigra pars compacta (SNc) and a high presynaptic accumulation of α-synuclein (α-syn) in the enlarged terminals. Mechanistic studies showed that VMP1 deficiency in the mDAergic neurons led to the increased number of microtubule-associated protein 1 light chain 3-labeled (LC3) puncta and the accumulation of sequestosome 1/p62 aggregates in the SNc neurons, suggesting the impairment of autophagic flux in these neurons. Furthermore, VMP1 deficiency resulted in multiple cellular abnormalities, including large vacuolar-like structures (LVSs), damaged mitochondria, swollen ER, and the accumulation of ubiquitin+ aggregates. Together, our studies reveal a previously unknown role of VMP1 in modulating neuronal survival and maintaining axonal homeostasis, which suggests that VMP1 deficiency might contribute to mDAergic neurodegeneration via the autophagy pathway.

Highlights

Vacuole membrane protein 1 (VMP1), an endoplasmic reticulum (ER)-resident protein, has attracted attention recently owing to its essential role on mediating autophagy
We found that the total distance traveled, vertical movement, and stereotypic movement were significantly decreased in VMP1cKO mice at the 63rd postnatal day compared to the age-matched VMP1cWT mice (Fig. 2A–E), demonstrating that VMP1cKO mice developed progressive motor deficits
Video recording at the 63rd postnatal day showed that VMP1cKO mice displayed an unbalanced, trembling walking pattern, which was not observed in VMP1cWT mice (Supplementary Videos 1 and 2)

Summary

Introduction

Vacuole membrane protein 1 (VMP1), an endoplasmic reticulum (ER)-resident protein, has attracted attention recently owing to its essential role on mediating autophagy. Once mutated at the ATG domain VMP1 fails to induce microtubule-associated. VMP1 depletion reversely promotes the accumulation of LC3-labeled autophagic structures at ER in the VMP1 knockout (KO) mammalian cells upon aberrant nutrient conditions[3], suggesting that VMP1 may play an important role in the autophagic process by regulating interactions between ER and autophagic-isolation membrane[4]. These studies indicate that VMP1 deficiency inhibits autophagosome maturation, disrupts the association with ER and blocks the fusion with lysosome[4]. The research in Dictyostelium[5], plants[6], and Chlamydomonas[7] indicates that VMP1 is highly involved in the processes of protein secretion, phagocytosis, osmoregulation, and cytokinesis to mediate the diverse cellular process

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